期刊
HUMAN MOLECULAR GENETICS
卷 14, 期 3, 页码 357-372出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddi032
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资金
- NIA NIH HHS [AG012466] Funding Source: Medline
- NIEHS NIH HHS [V45 ES012078] Funding Source: Medline
- NINDS NIH HHS [NS002116] Funding Source: Medline
Huntington's disease (HD) is caused by expansion of a polyglutamine tract near the N-terminal of huntingtin. Mutant huntingtin forms aggregates in striatum and cortex, where extensive cell death occurs. We used a Drosophila polyglutamine peptide model to assess the role of specific cell death regulators in polyglutamine-induced cell death. Here, we report that polyglutamine-induced cell death was dramatically suppressed in flies lacking Dark, the fly homolog of human Apaf-1, a key regulator of apoptosis. Dark appeared to play a role in the accumulation of polyglutamine-containing aggregates. Suppression of cell death, caspase activation and aggregate formation were also observed when mutant huntingtin exon 1 was expressed in homozygous dark mutant animals. Expanded polyglutamine induced a marked increase in expression of Dark, and Dark was observed to colocalize with ubiquitinated protein aggregates. Apaf-1 also was found to colocalize with huntingtin-containing aggregates in a murine model and HD brain, suggesting a common role for Dark/Apaf-1 in polyglutamine pathogenesis in invertebrates, mice and man. These findings suggest that limiting Apaf-1 activity may alleviate both pathological protein aggregation and neuronal cell death in HD.
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